The multifunctional nature of transforming growth factor-beta (TGF-beta) underlies its involvement in many pathologies, including neurodegenerative diseases. Changes that may occur in the expression of protein and mRNA for TGF-beta isoforms in response to various disease states and tissue treatments are being investigated using immunohistochemistry and Northern blot techniques. There is increased expression of TGF-beta2 in astrocytes in brains from patients with familial and sporadic Azlheimer's disease (AD) when compared to controls. There is also expression of TGF-beta2 in neurons exhibiting neurofibrillary tangles. This increased expression is also found in eight other neurodegenerative diseases. We are now investigating changes in TGF-beta expression in two recently developed transgenic mouse models of AD. In primary cultures of rat embryo hippocampal neurons, TGF-betas can protect against the damaging effects of treatment with beta-amyloid peptide (beta-AP). TGF-beta treatment before addition of beta-AP causes a two- to three-fold increase in cell survival. Similar protective effects are seen in hNT cells, a terminally differentiated human neuronal cell line generated by treating the human teratocarcinoma NT2/D1 cell line with retinoic acid. The protective effects of TGF-beta are not observed in the parent NT2/D1 cells. The protective effects correlate with induction of the expression of the TGF-beta type II receptor that occurs as the NT2/D1 cells differentiate to hNT cells. We are now examining the expression of TGF-beta receptors in AD.